Phentermine

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Phentermine
Fentermina.svg
Phentermine-3d-CPK.png
Clinical data
Trade namesAdipex-p, Duromine, Metermine, Suprenza, others
Synonymsα-methyl-amphetamine
α,α-dimethylphenethylamine
AHFS/Drugs.comMonograph
MedlinePlusa682187
License data
Pregnancy
category
  • AU: B3
  • US: X (Contraindicated)
Dependence
liability
Limited[2]
Addiction
liability
Low[1]
Routes of
administration
By mouth
Drug classAppetite suppressant[3]
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityHigh (almost complete)[4]
Protein bindingApproximately 96.3%
MetabolismLiver[4]
Elimination half-life25 hours, urinary pH-dependent[4]
ExcretionUrinary (62–85% unchanged)[4]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.004.112 Edit this at Wikidata
Chemical and physical data
FormulaC10H15N
Molar mass149.233 g/mol g·mol−1
3D model (JSmol)
  (verify)

Phentermine (phenyl-tertiary-butylamine), sold under the brand name Ionamin among others, is a medication used together with diet and exercise to treat obesity.[3] It is taken by mouth for up to a few weeks.[3] After a few weeks the beneficial effects no longer occur.[3] It is also available as the combination phentermine/topiramate.[5]

Common side effects include a fast heart beat, high blood pressure, trouble sleeping, dizziness, and restlessness.[3] Serious side effects may include pulmonary hypertension, valvular heart disease, and abuse.[3] Use is not recommended during pregnancy or breastfeeding.[6] Use is not recommended together with SSRIs or MAO inhibitors.[3] It works as an appetite suppressant likely as a result of being a CNS stimulant.[3] Chemically, phentermine is a substituted amphetamine.[7]

Phentermine was approved for medical use in the United States in 1959.[3] It is available as a generic medication.[3] The wholesale cost of a month supply in the United States is about US$2.55.[8] In 2016 it was the 226th most prescribed medication in the United States with more than 2 million prescriptions.[9] Phentermine was withdrawn from the market in the United Kingdom in 2000 while the combination medication fen-phen, of which it was a part, was withdrawn from the market in 1997 due to side effects.[10]

Medical uses[edit]

Phentermine is used for a short period of time to promote weight loss, if exercise and calorie reduction are not sufficient, and in addition to exercise and calorie reduction.[4][11]

Phentermine is approved for up to 12 weeks of use and most weight loss occurs in the first weeks.[11] However, significant loss continues through the sixth month and has been shown to continue at a slower rate through the ninth month.[12]

Contraindications[edit]

Phentermine use is contraindicated in those who:[4][11]

Adverse effects[edit]

Rare cases of pulmonary hypertension and cardiac valvular disease have been reported.[11] Tolerance usually occurs; however, risks of dependence and addiction are considered negligible.[12][13] People taking phentermine may be impaired when driving or operating machinery.[11] Consumption of alcohol with phentermine may produce adverse effects.[11]

There is currently no evidence regarding whether or not phentermine is safe for women who are pregnant.[4][11]

Other adverse effects include:[4][11]

  • Cardiovascular effects like palpitations, tachycardia, high blood pressure, precordial pain; rare cases of stroke, angina, myocardial infarction, cardiac failure and cardiac arrest have been reported.
  • Central nervous system effects like overstimulation, restlessness, nervousness, insomnia, tremor, dizziness and headache; there are rare reports of euphoria followed by fatigue and depression, and very rarely, psychotic episodes and hallucinations.
  • Gastrointestinal effects include nausea, vomiting, dry mouth, cramps, unpleasant taste, diarrhea, and constipation.
  • Other adverse effects include trouble urinating, rash, impotence, changes in libido, and facial swelling.

Interactions[edit]

Phentermine may decrease the effect of drugs like clonidine, methyldopa, and guanethidine. Drugs to treat hypothyroidism may increase the effect of phentermine.[11]

Mechanism of action[edit]

Phentermine.jpg

Phentermine has some similarity in its pharmacodynamics with its parent compound, amphetamine, as they both are TAAR1 agonists,[14] where the activation of TAAR1 in monoamine neurons facilitates the efflux or, release into the synapse, of these neurochemicals; at clinically relevant doses, phentermine primarily acts as a releasing agent of norepinephrine in neurons, although, to a lesser extent, it releases dopamine and serotonin into synapses as well.[13][15] Phentermine may also trigger the release of monoamines from VMAT2, which is a common pharmacodynamic effect among substituted amphetamines. The primary mechanism of phentermine's action in treating obesity is the reduction of hunger perception, which is a cognitive process mediated primarily through several nuclei within the hypothalamus (in particular, the lateral hypothalamic nucleus, arcuate nucleus, and ventromedial nucleus). Outside the brain, phentermine releases norepinephrine and epinephrine – also known as noradrenaline and adrenaline respectively – causing fat cells to break down stored fat as well.

History[edit]

In 1959, phentermine first received approval from the United States FDA as an appetite-suppressing drug.[16] Eventually a hydrochloride salt and a resin form became available.[16]

Phentermine was marketed with fenfluramine or dexfenfluramine as a combination appetite suppressant and fat burning agent under the popular name fen-phen. In 1997, after 24 cases of heart valve disease in fen-phen users, fenfluramine and dexfenfluramine were voluntarily taken off the market at the request of the FDA.[17] Studies later showed nearly 30% of people taking fenfluramine or dexfenfluramine for up to 24 months had abnormal valve findings.[18]

Phentermine is still available by itself in most countries, including the US.[16] However, because it is similar to amphetamine, it is classified as a controlled substance in many countries. Internationally, phentermine is a schedule IV drug under the Convention on Psychotropic Substances.[19] In the United States, it is classified as a Schedule IV controlled substance under the Controlled Substances Act. In contrast, amphetamine preparations are classified as Schedule II controlled substances.[20]

A company called Vivus developed a combination drug, phentermine/topiramate that it originally called Qnexa and then called Qsymia, which was invented and used off-label by Thomas Najarian, who opened a weight-clinic in Los Osos, California in 2001; Najarian had previously worked at Interneuron Pharmaceuticals, which had developed one of the fen-phen drugs previously withdrawn from the market.[21] The FDA rejected the combination drug in 2010 due to concerns over its safety.[21] In 2012 the FDA approved it after Vivus re-applied with further safety data.[22] At the time, one obesity specialist estimated that around 70% of his colleagues were already prescribing the combination off-label.[21]

Chemistry[edit]

Phentermine is a substituted amphetamine which has a methyl group on amphetamine's alpha carbon.[7] It is a positional isomer of methamphetamine and other methylamphetamines. The molecular formula of phentermine is C10H15N.

Synthesis[edit]

Phentermine can be produced from benzaldehyde and 2-nitropropane as follows:[23][24]

  1. Benzaldehyde and 2-nitropropane are cross-reacted in a variant of the Henry reaction
  2. The nitro group is reduced with hydrogen gas over Raney nickel catalyst
  3. The hydroxyl group is chlorinated with thionyl chloride to yield 2-amino-1-chloro-2-methyl-1-phenylpropane
  4. This is reduced with hydrogen gas over a palladium on magnesium glycinate catalyst to yield the product, phentermine

Society and culture[edit]

Names[edit]

Phentermine is contracted from phenyl-tertiary-butylamine.

Phentermine is marketed under many brand names and formulations worldwide, including Acxion, Adipex, Adipex-P, Duromine, Elvenir, Fastin, Lomaira (phentermine hydrochloride), Panbesy, Qsymia (phentermine and topiramate), Razin, Redusa, Sentis, Suprenza, and Terfamex.[25]

References[edit]

  1. ^ Sadock, Benjamin J.; Sadock, Virginia A. (2010). Kaplan and Sadock's Pocket Handbook of Clinical Psychiatry. 435: Lippincott Williams & Wilkins. ISBN 9781605472645.
  2. ^ Tarascon Pocket Pharmacopoeia 2017 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. 2016. p. 7. ISBN 9781284118971.
  3. ^ a b c d e f g h i j "Phentermine Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 13 April 2019.
  4. ^ a b c d e f g h "METERMINE (Phentermine)" (PDF). TGA eBusiness Services. iNova Pharmaceuticals (Australia) Pty Limited. 22 July 2013. Retrieved 16 November 2013.
  5. ^ "Phentermine and topiramate Uses, Side Effects & Warnings". Drugs.com. Retrieved 13 April 2019.
  6. ^ "Phentermine Use During Pregnancy". Drugs.com. Retrieved 13 April 2019.
  7. ^ a b Hagel JM, Krizevski R, Marsolais F, Lewinsohn E, Facchini PJ (2012). "Biosynthesis of amphetamine analogs in plants". Trends Plant Sci. 17 (7): 404–412. doi:10.1016/j.tplants.2012.03.004. PMID 22502775.
  8. ^ "NADAC as of 2019-02-27". Centers for Medicare and Medicaid Services. Retrieved 3 March 2019.
  9. ^ "The Top 300 of 2019". clincalc.com. Retrieved 22 December 2018.
  10. ^ Bagchi, Debasis; Preuss, Harry G. (2012). Obesity: Epidemiology, Pathophysiology, and Prevention, Second Edition. CRC Press. p. 314. ISBN 9781439854259.
  11. ^ a b c d e f g h i "Phentermine label at FDA" (Last updated: January 2012). FDA. Retrieved 13 October 2016.
  12. ^ a b Glazer G (August 2001). "Long-term Pharmacotherapy of Obesity 2000". Archives of Internal Medicine. 161 (15): 1814–1824. doi:10.1001/archinte.161.15.1814. ISSN 0003-9926.
  13. ^ a b Haslam D (February 2016). "Weight management in obesity – past and present". International Journal of Clinical Practice. 70 (3): 206–217. doi:10.1111/ijcp.12771. ISSN 1368-5031. PMC 4832440. PMID 26811245.
  14. ^ Barak LS, Salahpour A, Zhang X, Masri B, Sotnikova TD, Ramsey AJ, Violin JD, Lefkowitz RJ, Caron MG, Gainetdinov RR (September 2008). "Pharmacological characterization of membrane-expressed human trace amine-associated receptor 1 (TAAR1) by a bioluminescence resonance energy transfer cAMP biosensor". Mol. Pharmacol. 74 (3): 585–94. doi:10.1124/mol.108.048884. PMC 3766527. PMID 18524885. we confirmed agonistic activity at human TAAR1 of several other compounds, including the trace amines octopamine and tryptamine, the amphetamine derivatives l-amphetamine, d-methamphetamine, (+)-MDMA, and phentermine, and the catecholamine metabolites 3-MT and 4-MT (Bunzow et al., 2001; Lindemann and Hoener, 2005; Reese et al., 2007; Wainscott et al., 2007; Wolinsky et al., 2007; Xie and Miller, 2007; Xie et al., 2007).
  15. ^ Rothman RB, Baumann MH, Dersch CM, et al. (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707.
  16. ^ a b c Ryan, Donna A.; Bray, George A. (2014). "Sibutramine, Phentermine, and Diethylproprion: Sympathomimetic Drugs in the Management of Obesity". In Bray, George A.; Bouchard, Claude (eds.). Handbook of Obesity - Volume 2 Clinical Applications, Fourth Edition (4th ed.). Hoboken: Taylor and Francis. p. 234. ISBN 9781841849829.
  17. ^ "FDA Announces Withdrawal Fenfluramine and Dexfenfluramine (Fen-Phen)". Fda.gov. Retrieved 12 July 2013.
  18. ^ Weigle, DS (June 2003). "Pharmacological therapy of obesity: past, present, and future". The Journal of Clinical Endocrinology and Metabolism. 88 (6): 2462–9. doi:10.1210/jc.2003-030151. PMID 12788841.
  19. ^ Convention on Psychotropic Substances (PDF file) Archived 14 March 2014 at the Wayback Machine
  20. ^ Rueda-Clausen, CF; Padwal, RS; Sharma, AM (August 2013). "New pharmacological approaches for obesity management". Nature Reviews. Endocrinology. 9 (8): 467–78. doi:10.1038/nrendo.2013.113. PMID 23752772.
  21. ^ a b c Pollack, Andrew (16 February 2012). "Diet Treatment, Already in Use, to Get F.D.A. Review". The New York Times.
  22. ^ "FDA approves weight-management drug Qsymia". FDA. 17 July 2012.
  23. ^ U.S. Patent 2,408,345
  24. ^ U.S. Patent 2,590,079
  25. ^ "International brands for phentermine". Drugs.com. Retrieved 13 October 2016.

External links[edit]